Process for the preparation of trivalent iron complexes with mono-, di- and polysaccharide sugards

ABSTRACT

Process for the preparation of trivalent iron complexes with mono-, di- and polysaccharide sugars, consisting of the activation of the sugar by oxidation with nascent bromine generated in situ by reaction between an alkaline or alkaline earth bromine and an alkaline hypochlorite, the complexation of the activated sugar in solution with a ferric salt dissolved in an aqueous solution, the purification of the resulting solution through ultrafiltration and finally the stabilization of the trivalent iron-sugar complex by heating at a temperature between 60° C. and 100° C. for a period between 1 and 4 hours at a pH between 9.0 and 11.0.

AMBIT OF THE INVENTION

The aim of the present invention relates to the synthesis of trivalentiron (III) complexes with mono-, di- and polysaccharide sugars. Theproducts obtainable according to the method of the present patent canbe: iron gluconate, iron polymaltose, iron dextran, iron saccharatestabilized with sucrose, or novel complexes such as the iron lactate orother.

These derivatives can be advantageously used in the therapy of differentpathologies, such as

-   functional iron deficiency in patients suffering from a renal    chronic failure;-   bad absorption of the iron due to intestinal diseases;-   chronic blood loss also together with erythropoietin;-   constitutional anemia.

The synthesis of the trivalent iron complexes with sugars is known sincemany years even if, still today, the research in this field is active,as several methods used for the synthesis lead to not much stablecomplexes or said methods are difficult to apply.

It should be remembered that the iron complexes are produced above allfor being orally, intramuscularly or intravenously administered topatients or animals, as suitable drugs for preventing or treatingpathologies from iron deficiency.

For this reason, these iron derivatives must have some fundamentalcharacteristics, such as: physical-chemical stability over time, safetyin the administration, low toxicity, good bioavailability and easinessof production.

As for the toxicity and the bioavailability, it is known that thebivalent iron has an optimal oral bioavailability but has as well anintrinsic toxicity which is expressed at a gastrointestinal and hepaticlevel, above all due to the accumulation. For these reasons, thebivalent iron salts are not much used in therapy, even if the productioncost is limited and can be orally administered, moreover the sideremylevel reached with the therapy must always be accurately monitored. Onthe contrary, the trivalent iron is less toxic when is administered inproducts which effectively stabilize the iron through complexation ofthe same, as it occurs at a biological level for example by theferritin, which complexes the iron but maintains a good capability ofgiving it to the biological systems assigned for transporting or usingthe same. The trivalent iron is a strong oxidant and so, if not trappedin systems capable of storing and giving it only when effectivelyrequired by the endocrine system, it can seriously damage some importantorgans, such as the liver and the kidneys.

From above, it is evicted that the complex must have an opportunestability which has to ensure, from one side, the required preservationof the product in vials and from the other side, the equally importantcapability of delivering the iron only to the proteinic systems intendedto the depot storage or the transport of the iron itself. Therefore, thestability of the Fe⁺⁺⁺-sugar complex is one of the most importantfeatures, because from this depends not only the shelf life of theselected pharmaceutical form but also the bioavailability of thecomplexed iron. A poorly stable complex will cause great problems, notonly about the administration but also the toxicity, as it will deliverthe iron to all the biological Systems capable of producing complexeswith the iron, for example the hematic proteins, by subtracting it tothe biological systems specifically assigned to the transport and thestorage of the same.

It has been noted that the trivalent iron complex with the sugars isstable if some essential conditions are respected:

-   1) physical-chemical homogeneity of the ferric hydroxide-   2) Use of polysaccharides with a low content of low molecular    weights-   3) Sugars with the activated glucoside terminus.

1) The first condition is that the ferric hydroxide must be ahomogeneous product, namely it must not be a mixture of polymorph formswhich can complex the iron in a different way, each with a differentstability. Furthermore, the ferric hydroxide must not be charged andtherefore it must not be even partially salified with anions, a thingthat can happen when one tries to isolate it from a solution of a saltthereof by basic treatment.

For example, the precipitation, in addition to Fe(OH)₃, of FE(OH)₂Cl, orNaFe(OH)₂CO and so on can occur, obtaining mixtures of hydroxides whichmake difficult the complex formation and decrease the stability thereof.

Erni I, et al. Arzneim.-Forsch./Drug. Res. 34, (II), No. 11 p.1555-1558, 1984, state that the precipitated and isolated ferrichydroxide, even if in controlled and repetitive reaction conditions,always consists of different kinds of hydroxides.

All the above is confirmed by the fact that the ferric hydroxide, whichis reacted with the sugar, is only partly solubilized and forms thecomplex by remaining partly as a bottom body or, as it often happens,precipitating the complex after a time. Therefore, in order to obtain aneffective and repeatable reaction for the complex formation, it isnecessary to carry out the iron hydration reaction in a solution,allowing the reaction itself to slowly re-equilibrate in the presence ofsugar.

Moreover, everyone knows that the isolation and the purification of theferric hydroxide are two steps that have a remarkable productivedifficult.

2) The second condition is that the sugar should be activated, namelythe end group should not be in form of aldehyde or hemiacetal. In fact,this end group besides being unable to participate to the formation ofthe complex, can intervene by partly reducing the trivalent ironbringing it to the lower oxidation state of bivalent iron, which islargely bioavailable also by mouth, but just for this reason becomesparticularly harmful for the organism, requiring a constant monitoringof the hematic levels.

Therefore, if the polyhydroxylate compound that one whishes to use forforming the complex with the iron contains some reducing end groups,such as an aldohexose sugar, since such groups can destabilize thecomplex, it is necessary that the aldehyde group, also in form ofhemiacetal form, is transformed in a stable group which can contributeto the formation and stabilization of the complex with the Fe. The moresuitable transformations of the aldehyde end group are the reduction toan alcohol group or the oxidation to a carboxy group. This operation iscalled sugar “activation”.

The conditions applied to various synthesis described in the patents donot foresee an alteration of the sugar, however the complex formation iscarried out in a basic environment at high temperature, whereby in suchconditions the end groups can likely undergo a modification similar tothe one described by Cannizzaro for the adehydes subjected todismutation in a basic environment. However, in these conditions thesugar itself can undergo different degradation reactions.

In many other patents, sugar previously activated in a basic environmentat high temperature is used. These conditions, even if less destroyingthan the preceding ones as the reaction takes place in absence of iron,lead however to a mixture wherein, together with a sugar in which theacetal group is partly oxidized to acid and partly reduced to 7 alcohol,modified and hydrolized sugars can be obtained, as it can be ascertainedby the dark colour of the solution and the strong caramel smell.

Other patents report a sugar activation through oxidation with bromine,bromites or chlorites which however represent reagents of a difficulthandling, preparation and storage. Moreover, it is known that the use ofsuch reagents, if not carried out in controlled pH conditions, reagentconcentration and temperature, can lead to oxidation reactions drivenwith partial hydrolysis of the end sugar.

3) The third condition, in case of polysaccharide sugars, is that thesugar used should not contain very low molecular weight fractions, asthese are able to complex a large quantity of iron but are unable toensure the solubility of the complex. In fact, gelation phenomena of thesolution or precipitation of a bottom body which effectively preventsthe parenteral administration of the preparation can occur over time inpreparations with a high content of very low molecular weights.

Generally, iron complexes with activated mono- or disaccharide sugarsare stabilized by increasing the pH and introducing in the preparationlarge quantities of sugar. These complexes have a pH between 8.0 and12.0 and therefore are administered only intravenously. Also sugars withtoo high molecular weights are harmful for the formation of the complexwith the iron. Especially in case of dextran, the very high molecularweights can cause anaphylactic shock and increase the general toxicityof the complex, above all when administered by parenteral route.

It is therefore necessary to evaluate with a great attention thecontents of high and low molecular weights, and for this reason thereare some patents which claim sugars with particular molecular weights orranges of molecular weight.

By analyzing the state of the art, it is possible to find severalpatents which report different synthesis systems wherein the threeconditions above considered are completely or partly disregarded.

Many patents report, for example, the synthesis of iron/polysaccharidescomplexes starting from isolated ferric hydroxide, such as the U.S. Pat.No. 4,180,567 wherein dialyzed ferric hydroxide and non-activateddextran, dextrins or glucose are used as complexing agents, or thepatent Fr 1,462,959, wherein ferric hydroxide and sorbitol are Used ascomplexing agents. Also in the U.S. Pat. No. 4,749,695 ferric hydroxideis reacted. with dextran at a high temperature, while in the patent GB694,452 the isolated ferric hydroxide is reacted with cane sugar. Theobtained product is precipitated and heated in a high temperature oven,and such synthesis leads to non-standardized and sometimes even toxicproducts.

On the contrary, there are several patents which, for obtaining thecomplexes in question, use trivalent iron salts in an aqueous solution,then the sugar is added by simultaneously rising the pH and thetemperature. If the rising of the pH is gradually carried out, there canbe a re-balance between all the variously hydrated intermediatecompounds of the iron, namely, for example, starting from irontrichloride, by slowly increasing the pH a slow re-balance of FeCl₃ toFeCl₂OH then to FeCl(OH)₂ to Fe(OH)₃ or FeOOH is obtained, depending onthe final pH. It should be kept in mind that also other balanceintermediate forms are possible, such as NaFeCO₃(OH)₂ if hydrogencarbonate or carbonate is used for increasing the pH. As abovementioned, the obtainment step of the ferric hydroxide, which beinginsoluble precipitates together with their balance forms, isdeterminant. A sharp increase of the pH leads to the obtainment of aferric hydroxide which co-precipitates with all its balance components,since these latter are not able to re-balance themselves in favour ofthe end product, i.e. the ferric hydroxide.

In many patents the sugar is not activated before its reaction with theferric hydroxide, but it should be kept in mind that the aldohexosesugars, even if they have the aldehyde end group in form of hemiacetal,when subjected to a strong heating in a basic environment can undergo,besides a demolition action, also a dismutation reaction to thecorresponding acid and alcohol. This dismutation is an activation of thesugar which, also unintended, makes the sugar suitable to the formationof a stable complex with the ferric hydroxide. The negative side ofthese synthesis methods is the end product, which is a mixture ofproducts containing ferric hydroxide more or less complexed with sugarsat least partly decomposed or modified in an uncontrolled way. In fact,it is apparent that also by carefully carrying out these steps for theformation of the complexes, considering the different hydrolysis,demolition and activation reactions of the sugar which can occur in aconcomitant way, it is to be expected, of course, that the end productcontains iron complexes with more or less modified different sugarsspecies. Typical of these complexes is the caramel smell which comeswith the end product in solution meaning that a partial demolition ofthe same has been attained.

For example, the patent BE 787662 lies within this class of patents, asit claims a method for the synthesis of complexes obtained by reactingferric chloride hexahydrate in solution and a sugar included among a lowmolecular weight dextrin, maltose or glucose with a pH in the range from11.0-14.0 and at a temperature of 90° C.: during the reaction, a mixtureof ferric hydroxides precipitates and simultaneously the sugar is partlyhydrolized and dismutated, namely it also undergoes a process whichleads to its activation which however, taking place in the presence oftrivalent iron, can lead to an important level of hydrolysis products.

Therefore, with this kind of process there is, from one side, theapplication of a simpler methodology, but on the other side, the processis varying both for the obtainment of ferric hydroxide, which remainspartly not dissolved at the end of the reaction, and for thedegradation/activation of the sugar. In U.S. Pat. No. 2,820,740, theapplied methodology foresees a reaction between the dextran partlyhydrolized and ferric chloride or ferric citrate in the presence ofsodium carbonate at a temperature varying between 65 and 100° C. Thereremains some ferric hydroxide, which does not form the complex and whichis finally filtered and eliminated. This residue shows that the reactionfor obtaining the ferric hydroxide has been carried out in uncontrolledconditions and, as above mentioned, leads to a polymorph mixture offerric hydroxide.

In the patent GB 1,019,513, a depolimerized sugar, dextran, is used,wherein the aldehyde end group has been eliminated by reduction withNaBH4. The sugar became activated and is able to give a stable complex,even if it is necessary to completely eliminate the boron because of itstoxicity.

The ferric salt used is the ferric trichloride, to which a certainquantity of citric acid, which is an iron complexing agent, is added.

In the U.S. Pat. No. 2,885,393, depolimerized dextran is reacted andactivated with a ferric chloride solution brought to a pH of 2.3 withsodium carbonate, by heating the whole at 65° C. for 30 minutes.

The U.S. Pat. No. 4,180,567 claims the activation of sugars eitherthrough reduction with NaBH4 or through a basic treatment at pH10.5-11.3 for 1 hours at 95° C.-100° C. Such sugars are reacted withferric hydroxide dialyzed at high temperature, then the solution isconcentrated and the bottom body is filtered.

In the U.S. Pat. No. 4,599,405, a dextran with an average molecularweight equal to 5000 Daltons is reacted with ferric trichloride afterthe salt solution has been brought to pH 1.7 by slow addition of aNa₂CO₃ solution and subsequently NaOH is added up to pH 11.0 over 30minutes. A suspension is formed, which is heated at 100° C. for aboutone hour. The solid which does not form the complex is eliminated bycentrifugation and then the product is isolated by precipitation withsolvents. Also with this method, there is the formation of a mixture ofhydrated iron compounds which do not form completely soluble complexeswith the sugars. It should be noted that the high temperature used inthe formation of the complex, as also observed for other patents, canlead to the partial degradation/activation of the system which can bepointed out by the black colour of the obtained solution and by thecaramel smell.

In the U.S. Pat. No. 6,291,440, a complex obtained between ferrichydroxide and hydrogenated dextran with a molecular weight between 700and 1400 Daltons is claimed.

Dextran purification is carried out by membrane filtration, in order toeliminate both the high molecular weights which are responsible for theanaphylactic reactions and the very low molecular weights which areresponsible for the instability of the preparations.

The patent DK 129353 claims a method for forming the complex betweeniron and a dextran with a maximum molecular weight up to 50000 Daltons,preferably between 1000 and 10000 Daltons. The dextran has the endgroups oxidized to the corresponding acid, but the method for obtainingthe same is not disclosed.

In the publication of the patent application WO 00/30657 a low weightdextran is claimed, obtained by hydrolysis at pH 1.5 and at 90° C. Thedextran is fractionated by ultrafiltration with a cut off of 5000Daltons and after depolimerization, is further ultrafiltered using a cutoff between 350-800 Daltons, in order to eliminate the very low weights.On the obtained dextran, a reduction with NaBH₄ is carried out forreducing about the 15% of the end hemiacetal groups, and therefore theoxidation with NaClO of the remaining end groups is carried out. Theformation reaction of the complex is carried out at a pH of 1.6 when theiron chloride has been partly neutralized with sodium carbonate. Alsofor this patent, is not clear why the sugar, in this case the dextran,is added when more than 60% of the ferric chloride has already beentransformed in ferric hydroxide.

It is apparent that the presence, from the start, of the sugar not onlypromotes the complex formation during the transformation of the ferricchloride in ferric hydroxide, but it promotes the completetransformation of the iron salt in ferric hydroxide preventing theprecipitation of the partly hydrated iron.

Finally, the patent EP 0150085 claims a dextran with a molecular weightbetween 2000 and 6030 Daltons oxidized with sodium chlorite which,according to the inventors, oxidizes in a specific way the aldehyde endgroup differently from what stated by the U.S. Pat. No. 4,370,476wherein bromine is used for the oxidation and it is stated that alsosodium hypobromite, sodium bromite, chlorine, iodine, sodiumhypochlorite, sodium chlorite are likewise effective in the oxidation ofthe end groups of the dextran.

DESCRIPTION OF THE INVENTION

The aim of the present invention relates to a production process oftrivalent iron complexes with polyhydroxylated compounds, such as themono-, di- or polysaccharide sugars. The process includes differentsteps, the first of which consisting of the activation of the sugar. Itis known since long that the sugars having an aldehyde end group, alsoin form of hemiacetal form, can be oxidized through different methodsusing bromine or other reagents, such as bromites, chlorites,hypochlorites, hypoiodites, or bromides and gaseous halogens, such aschlorine gas in a basic environment. All these reagents are eitherdifficult to handle because of their dangerousness, see bromine andchlorine, or unstable, or they give rise to aspecific oxidationreactions, by oxidizing aldehydes and primary alcohols.

In the patent GB 289280, only the oxidation of glucose and galactose isdescribed, using bromides or iodides and chlorine in a strongly alkalineenvironment. The reaction is carried out at a temperature lower than 15°C. for avoiding the formed bromine from escaping from the environment.The chlorine is added all at once, this means that the environmentitself becomes saturated with chlorine, or rather hypochlorite, andtherefore both the bromine originating from the oxidation of thebromide, and the hypochlorite co-exist as sugar oxidants. This hinders aclean and complete reaction, as the hypochlorite is able to oxidize alsothe primary alcohol on the carbon in 6-position giving the glutaric acidand at the same time can hydrolize the complex sugars, such as thepolysaccharides. In the U.S. Pat. No. 6,498,269, the oxidation of evencomplex sugars in a strongly alkaline environment is reported, throughtreatment with halogen, generally gaseous chlorine, in the presence of acatalyst of the oxyammonium halide type, by obtaining a diacid as mainproduct.

Surprisingly, we have found that if the use of bromine as an oxidizingagent is desired, its dangerousness and handling difficulty are overcomeby producing such oxidizing agent in situ, slowly introducing sodiumhypochlorite instead of gaseous chlorine in a strongly acid environmentin the aqueous solution containing an alkaline or alkaline earth bromideand the sugar, at a pH between 5.0 and 11.0. The sugar activation isadvantageously industrially carried out because of the easiness ofhandling of the reagents and the repeatability of the reaction itself,as the oxidizing agent is produced in situ by treating a small quantityof an alkaline or alkaline earth metal bromide with an alkaline oralkaline earth metal hypochlorite, preferably sodium hypochlorite at apH in the range between 5.0 and 11.0, preferably between 7.0 and 9.0. Inthis way, the handling of reagents which require particular precautions,such as bromine, is avoided, and the activation reaction is furthercarried out in controlled conditions, in fact the bromide quantity usedis between 0.5% and 5% by weight of the sugar to be activated, thereforethe bromine quantity which is formed and is found in the reactionenvironment during the activation phase is really low with respect tothe quantity of sugar to be activated. The bromine quantity needed forthe sugar activation is produced instant by instant from the addition ofthe alkaline or alkaline earth hypochlorite, which is used in astoichiometric quantity with respect to the number of end aldehydesaccording to the reactions:

NaClO+2NaBr+H₂O→Br₂+NaCl+2NaOH  1)

Br₂+R—CHO+3NaOH→2NaBr+R—COONa+2H₂O  2)

Surprisingly, contrary to what happening by heating the sugar in analkaline environment with the dismutation of the aldehyde group and theconcomitant partial decomposition of the sugar, by our method anunivocal and absolutely clean reaction is obtained, with the specificoxidation of the end aldehyde.

In fact, by using stoichiometric quantities of hypochlorite with respectto the aldehyde end groups and adding it slowly, such that all the addedhypochlorite only serves for the bromide oxidation and an excess ofhypochlorite in solution is never present, the specific oxidation of thealdehyde group is obtained, maintaining unchanged the remaining chemicalstructure of the sugar used. The oxidation reaction is controlledthrough the pH adjustment. In fact, as the acid formation leads to aremarkable lowering of the pH and the consumption of hypochlorite, it issufficient to add the hypochlorite itself such that the pH is notlowered below 6.0 and the value of 10.0 is not exceeded. From the ¹H NMRspectrum which relates to the maltose oxidation, depicted in FIG. 1, itcan be noted the univocity of the structure obtained after theactivation reaction carried out according to the method of the presentinvention. Should, on the contrary, an excess of hypochlorite also bepresent, in addition to bromine in the reaction environment, oxidationsecondary reactions could occur, which would relate to other parts ofthe end sugar and to depolimerization phenomena. Therefore, it isimportant to maintain the reaction pH in the range between 5.0 and 12.0,preferably, between 7.0 and 9.0, since in this pH range the bromineconsumption takes place at a high rate leading to the oxidation of thealdehyde end group. With polisaccharide sugars, such as dextrins anddextrans, the activation reaction is carried out using, for thestoichiometric calculation, the average molecular weight or rather thevalue of dextrose equivalents, which shows the glucose equivalentscorresponding with the aldehyde end groups. In this way, the reaction iscarried out in strictly alkaline conditions and is of a simplerepeatability. If a quantity of alkaline or alkaline earth hypochloritedifferent from the stoichiometric quantity is added, a partial sugaractivation can be obtained, if a lower quantity of hypochlorite is used,with negative consequences on the stability of the end complex,otherwise, if a stoichiometric excess of hypochlorite is used, a furtheroxidation with a partial demolition of the end sugar can be obtained, inaddition to the described activation. Furthermore, in this latter case,a depolimerization of the sugar itself with formation of oligomers andlow molecular weights can be simultaneously obtained. In both cases, theend product is not homogeneous, being a mixture of sugars with adifferent chemical structure. The disadvantage of using a similarmixture of activated sugars is the obtainment of iron complexes with nonhomogeneous structure and stability.

In the ambit of the present invention, the preferred bromide is sodiumbromide and the preferred hypochlorite is sodium hypochlorite.

The second step of the process relates to the complexation reaction ofthe sugar activated with a proper salt of water soluble trivalent iron;the preferred salt for the execution of the present invention is theiron trichloride hexahydrate in a concentrated aqueous solution. For thegood result of the complexation reaction, it is necessary to initiallymix the activated sugar with the trivalent iron salt before the increaseof the pH, such that the sugar and the water can immediately stabilizethe trivalent iron facilitating the complete hydration reaction of theiron. This is pointed out in that, during the formation step of the ironhydroxide by slow addition of a base of alkaline metal, theprecipitation of the iron hydroxide itself never occurs, and thereaction always appears homogeneous. Only in the case of gluconic acid,when used in a concentrated solution at a pH between 3.0 and 4.0, thereis the precipitation of the ferric hydroxide already complexed by thesugar, as in fact for obtaining the complete solubilization of theprecipitate it is sufficient to increase the pH between 9.0 and 10.0.This fact is important since in no case a solid is precipitated or abottom body is left, as in the case of processes wherein the sugar isadded after an even partial increase of pH in order to obtain ferrichydroxide, or after complexation of the isolated ferric hydroxide. Theaddition of ferric salt to the early activated sugar solution does notlead to depolimerization phenomena of the sugar itself, even if theinitial pH is very acid, because the solution temperature is maintainedbelow 60°0. This step is critical, because the increase rate of the pHfor the obtainment of the ferric hydroxide must be suitable for carryingout the iron hydration reaction and, at the same time, promoting theformation of an initial Fe-sugar complex, so as to allow the completionof the hydration reaction of the iron itself without hydroxideprecipitation.

The third step of the process consists of the purification of the ferrichydroxide-sugar complex, even if such complex is still not beenstabilized by heating. Surprisingly, we have found that once the pH ofthe starting solution containing the activated sugar and the iron hasbeen increased in the range between 6.0 and 12.0, the ferrichydroxide-sugar complex, even if not yet stabilized, can beultrafiltered through a membrane with a proper cut-off. This processallows to remove all the salts formed during the hydration reaction ofthe iron, by obtaining a compound which can also be stored for a longtime, waiting to be subjected to following stabilization reactions.

Following to the purification, the trivalent iron-sugar complex issubjected to the stabilization step of the complex, wherein there is themodification of the ferric hydroxide in ferric oxy-hydroxide. Thistreatment takes place at a temperature between 60° C. and 100° C. for aperiod between 1 and 4 hours at a pH between 9.0 and 12.0. Thestabilization treatment can also be carried out before the purificationtreatment through ultrafiltration, obtaining the same result. Inparticular, this occurs in the production of the trivalent iron complexwith the activated glucose.

The complexes thus obtained and divided in glass vials or bottles can besuccessively sterilized by heating in autoclave at 125° C. for 30minutes without undergoing any stability modifications of the endcomplex. Finally, before the division in vials, the complexes betweenferric hydroxide and sugar can be blended with other sugars in a desiredproportion resulting, in some cases, in a further stabilization of thecomplex.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a depiction of the 1H NMR spectrum relating to glucoseoxidation.

FIG. 2 is a depiction of the 13C NMR spectrum relating to glucoseoxidation.

DETAILED DESCRIPTION OF THE INVENTION

The aim of the present invention consists of a process for thepreparation of complexes of trivalent iron (Fe³⁺) with mono-, di- andpolysaccharide sugars, complexes characterized by a goodphysical-chemical stability over time, low toxicity, use safety also byinjection and a good bioavailability.

Said process, characterized by execution easiness and safety, consistsof four steps:

-   1. activation of mono-, di- or polysaccharide sugar;-   2. complexation of the activated sugar with ferric hydroxide    generated in solution;-   3. purification of the ferric hydroxide/sugar complex still not    stabilized;-   4. stabilization of the ferric hydroxide/sugar complex.

The process is completed with the possible mixing of the obtainedcomplex with other sugars, a mixing which imparts a furtherstabilization to the complex, and with the packaging of the medicinalspeciality through sterilizing filtration, subdivision of the solutionin glass vials or bottles and final sterilization in autoclave at 125°C. for 30 minutes.

Preferred sugars in the execution of the present invention are: glucose,maltose, lactose, maltodextrins and dextrans.

The sugar activation is carried out by oxidation with nascent bromine.by dissolving the sugar in purified water at a concentration between 10%and 50% by weight, adding an alkaline or alkaline earth bromide,preferably Sodium bromide, in a quantity between 0.5% and 5% by weightbased on the sugar weight, bringing the pH of the solution to a valuebetween 5.0 and 11.0, preferably between 7.0 and 9.0, with sodiumhydroxide and adding under stirring at a temperature between 10° C. and60° C. in a period between 2 and 4 hours an aqueous solution containinga weighed stoichiometric quantity of an alkaline or alkaline earth metalhypochlorite, preferably sodium hypochlorite, with respect to thealdehyde end groups existing in the sugar. Preferred in the ambit of theinvention are sodium hypochlorite aqueous solutions containing about 12%by weight of active chlorine. Throughout the activation reaction of thesugar, the pH value is controlled and maintained in the fixed range,preferably between 7.0 and 9.0, by adjusting the addition rate of thehypochlorite. At the end of the reaction, to the solution of activatedsugar a concentrated aqueous solution of a ferric salt is added understirring, at a temperature between 15° C. and 60° C., so as thetrivalent iron/sugar weight ratio is in the range between 1:0.5 and 1:4.All the water soluble trivalent iron salts can be used, the greatlywater soluble ferric chloride hexahydrate being preferred in theexecution of the invention, whereby very concentrated aqueous solutionscan be obtained, for example aqueous solutions containing 40% by weightof ferric chloride.

After the addition of the ferric salt solution, to the mixture underconstant stirring an aqueous solution of sodium carbonate is added,preferably at 15% w/v, in a period between 1 and 6 hours with, so as toslowly increase the pH never exceeding the value between 2.3 and 2.7.

When this pH range has been reached, the stirring of the solution iscontinued for a time between 15 and 60 minutes and only subsequently, ina time between 1 and 2 hours, the pH of the solution is brought tovalues between 8.0 and 12.0 by addition of an aqueous solution of sodiumhydroxide, preferably at concentrations between 15% and 30% w/w.

The solution of the trivalent iron-sugar complex thus obtained issubjected to purification with removal of the salts and all the productswith a low molecular weight, by subjecting it to a membraneultrafiltration with a cut-off between 3000 and 5000 Daltons for themono- and disaccharide sugars, such as glucose, maltose, lactose, andwith a cut-off between 400 and 50000 Daltons for the polysaccharidesugars, such as dextrins and dextrans.

The ferric hydroxide-sugar complex thus purified is stabilized byheating of the solution which contains the same at a temperature between60° C. and 100° C., preferably between 75° C. and 95° C. for a timebetween and 4 hours at a pH between 9.0 and 12.0. The purified andstabilized solution can be stored for a long time in a cooledenvironment and when one desires to use it for the preparation ofmedicinal specialities, it has to be heated at a temperature between 60°C. and 100° C., preferably between 75° C. and 95° C. for a time between3 and 6 hours and therefore the end product can be isolated in differentways.

For example, it can be isolated in form of a powder through spraying orfreeze-drying, after having adjusted, if necessary, the pH of thesolution at values between 4.5 and 7.0. Otherwise, it is possible to addthe solution of the stabilized and purified complex with a further sugarquantity, also different from the one present in the complex, whichfurther stabilizes the solution, which can be divided in glass vials orbottles which are then sterilized at 125° C. for 30 minutes, preferablyat 121° C. for 20 minutes, or it can be freeze-dried, obtaining the endproduct in form of a powder.

In an advantageous embodiment, the process for the preparation oftrivalent iron complexes with mono-, di- and polysaccharide sugarsincludes the activation of the sugar. The sugar is obtained bydissolving the sugar in purified water at a concentration between 10%and 50% by weight, adding an alkaline or alkaline earth bromide in aquantity between 0.5% and 5% by weight based on the sugar weight,bringing the pH of the solution to a value between 5.0 and 11.0 andadding under stirring in a time between 2 and 4 hours, at a temperaturebetween 10° C. and 60° C., an alkaline or alkaline earth metalhypochlorite in aqueous solution in a stoichiometric quantity withrespect to the aldehyde end groups present in the sugar, if notbranched; in the specific case of the dextran, a hypochlorite quantitycorresponding with the double of the moles is used.

Subsequently, the activated sugar complexation, is obtained by addingthe solution of activated sugar under stirring, at a temperature between15° C. and 60° C., with an aqueous solution of a ferric salt, such thatthe weight ratio of iron to sugar is between 1:0.5 and 1:4 (from 1:0.5to 1:5), adding in a time between 1 a 6 hours, an aqueous solution ofsodium carbonate in order to bring the pH to a value between 2.3 and2.7, maintaining constant the pH in this range of values for a timebetween 15 and 60 minutes, and therefore bringing the pH to valuesbetween 8.0 and 12.0 by addition of a sodium hydroxide aqueous solution.Subsequently, the complex between ferric hydroxide and sugar is purifiedby ultrafiltration of the solution. Finally, the complex is stabilizedby heating of the ultrafiltered solution at a temperature between 60° C.and 100° C. for a time between 1 and 4 hours at a pH between 9.0 and12.0. In the case of dextran, the heating takes place for a minimum of 5hours. For example, the sugars are selected from glucose, maltose,lactose, maltodextrins and dextrans. The bromide is sodium bromide. ThepH of the activation reaction of the sugar is between 7.0 and 9.0. Thehypochlorite is sodium hypochlorite and the ferric salt is ferricchloride hexahydrate. The stabilization temperature of the complex isbetween 75° C. and 95° C. For example, the ultrafiltration is carriedout with a membrane with a cut-off between 3000 and 5000 Daltons for theglucose, maltose and lactose, while for maltodextrins and dextrans witha cut-off 400 in order to remove the salts and with a cut-off between30000 and 50000 Daltons in order to remove the low molecular weights.

For example, the stabilization treatment of the trivalent iron-gluconicacid complex is carried out before the purification treatment. Thecomplexes which can be obtained are for example ferric gluconate, thecomplex between iron hydroxide and maltose, the complex between ironhydroxide and lactose, the complex between iron hydroxide andmaltodextrins, the complex between iron hydroxide and dextran.

The enclosed FIG. 1 relates to activated glucose, while the enclosedFIG. 2 relates to glucose as such.

The following examples constitute a further illustration of the aim ofthe invention and are not to be intended as a limitation thereof.

EXAMPLE 1 Preparation of Ferric Gluconate

50 grams of glucose are dissolved under stirring in 740 ml of purifiedwater, and to the obtained solution 0.5 g. of sodium bromide are addedby simultaneously bringing the pH of the solution to a value between 7.0and 9.0 with a sodium hydroxide solution.

Over two hours, 164 g. of 12% active chlorine sodium hypochloritesolution are added, a quantity corresponding with a molar weight 1:1with respect to the glucose, by maintaining the pH value between 7.0 and9.0 and, at the end of the addition, the stirring is continued for other30 minutes. The control of the accomplished execution is carried outthrough HPLC or through polarimetric readings. The oxidation of glucoseto gluconic acid is obtained, as it can be verified by the 13C NMRspectrum depicted in FIG. 1.

The solution of gluconic acid is brought to a temperature between 16° C.and 20° C. and is added with 416 g. of a 40% ferric trichloride solutionat 40% by weight (iron/sugar ratio=1:0.87 w/w). The stirring iscontinued for a complete homogenization of the solution and in about twohours a 15% w/v sodium carbonate solution is added, until bringing thepH at a value between 2.3 and 2.7.

Once such value has been reached, the solution is maintained understirring for a time of 30 minutes by controlling that the pH remainsbetween 2.3 and 2.7. Subsequently, with a solution of sodium hydroxideat 15% w/v, the pH is brought to 11.0±0.5 over 1 hour, and during theincrease of the pH between 3.0 and 4.0 the formation of a precipitatecomprised of ferric hydroxide-gluconic acid complex occurs, which tendsto solubilize while the pH increases until a complete solubilization ata pH above 9.0.

A brown-coloured solution is obtained, which has no solids in suspensionand is brought to the temperature of 85±2° C. and maintained under thisconditions for 2 hours. At the end of the stabilization reaction of thecomplex, the obtained solution is purified from the salts through anultrafiltration system equipped with a membrane with a cut-off of 3000Daltons.

The resulting solution purified from the salts, brought to a pH of10.5±5, can be stored in a cooled environment and, before itspharmaceutical use, is again heated at a temperature of 90±2° C. for aperiod of 4 hours. The ferric gluconate is isolated by spraying,obtaining a yield higher than 85%, computed on the starting iron.

The physical-chemical features of the complex are the following:

-   Average Molecular Weight (Mw)=43347 Daltons-   Numerical Molecular Weight (Mn)=30495 Daltons-   Polydispersibility=1.4-   Fe3+ Content=48.6%

The molecular weights have been determined using the gel-permeationchromatography method, described on page 1065 by the United StatesPharmacopoeia (USP) 28′ Ed., which uses 2 columns in series TOSO HAAScolumn TSK-GEL G5000PWXL 30 cm×7.8 cm ID+TOSO HAAS column TSK-GEL 2500PWXL 30 cm×7.8 cm ID and dextrans with a known average molecular weightMw as a standard, and with the following molecular weights at the top ofthe peak, expressed in Daltons: 4410, 9890, 21400, 43500, 66700, 123500,196300, 276500.

EXAMPLE 2 Preparation of Ferric Gluconate

The ferric gluconate complex can be obtained using the same methodologyof the example 1, starting from commercial gluconic acid and ferricchloride.

24.5 grams of sodium gluconate are dissolved in 120 ml of purified waterand to the obtained solution 205 g. of a 40% wt ferric chloride solution(iron/sugar ratio=1:0.87 w/w), keeping under stirring until a completehomogenisation of the reaction mixture is reached.

The solution temperature is brought between 16° C. and 20° C. and over 2hours a 15% w/v sodium carbonate solution is added, to bring the pH ofthe solution at values between 2.3 and 2.7.

When such value has been reached, the solution is maintained understirring for a period of 30 minutes, by controlling that the pH remainsbetween 2.3 and 2.7.

Subsequently, with a 15% w/v sodium hydroxide solution, the pH isbrought to 11.0±0.5 over 1 hour, during this step with a pH between 3.0and 4.0 there is the formation of a precipitate, formed by a ferrichydroxide-gluconic acid complex, which solubilizes while the pH isincreased until a complete solubilization at a pH above 9.0.

A brown-coloured solution is obtained, which has no solids in suspensionand is brought to the temperature of 85±2° C. and maintained under thisconditions for 2 hours. At the end of the stabilization reaction of thecomplex, the obtained solution is purified from the salts through anultrafiltration system equipped with a cut-off membrane of 3000 Daltons.

The resulting solution purified from the salts, brought to a pH of10.5±5, can be stored in a refrigerated environment and, before itspharmaceutical use, is again heated at a temperature of 90° C. for aperiod of 4 hours. The ferric gluconate is isolated as such byfreeze-drying, obtaining a yield above 85% computed on the startingiron. The physical-chemical features of the complex, with the molecularweights determined according to the methodology described in the example1, are the following:

-   Average Molecular Weight (Mw)=53745 Daltons-   Numerical Molecular Weight (Mn)=30976 Daltons-   Polydispersibility=1.7-   Fe³⁺ Content=48.5%

EXAMPLE 3 Preparation of the Ferric Hydroxide/Maltose Complex

60 grams of maltose are dissolved in 200 ml of purified water, to thesolution thus obtained 0.6 g. of sodium bromide are added and the pH ofthe solution is brought to a value between 7.0 and 9.0 with a sodiumhydroxide aqueous solution.

Over two hours, 98.5 g. of 12% active chlorine sodium hypochlorite areadded, corresponding with the stoichiometric quantity with respect tothe aldehyde end groups, by maintaining the pH value between 7.0 and9.0. At the end of the addition, the stirring is continued for 30minutes and the control of the accomplished activation is carried outthrough HPLC by detecting the residual maltose and activated maltoseratio.

To the activated maltose solution, brought at a temperature between 16°C. and 20° C., 257 g. of a 40% wt (iron/sugar ratio=1:1.7 w/w) are addedcontinuing the stirring until a complete homogenization of the reactionmixture. Therefore, to the obtained solution a 15% w/v sodium carbonatesolution is added over 3 hours, so as to slowly bring the pH at a valuebetween 2.3 and 2.7.

When this value has been reached, the solution is maintained understirring and in these conditions over 15 minutes, by checking that thepH value remains between 2.3 and 2.3, and therefore the pH value isbrought to 10.5±0.5 over 1 hour, adding a 15% w/v. sodium hydroxidesolution. The precipitation of iron hydroxide never occurs, neither inform of a complex. The obtained solution is purified from the saltsthrough an ultrafiltration system equipped with a membrane with acut-off of 3000 Daltons.

The resulting solution purified from the salts is brought to a pH of11.5±0.5 and heated at a temperature of 75° C.±2 for a period of 2hours, then the complex is isolated by freeze drying.

The physical chemical features of the complex, with the molecularweights determined according to the methodology described in the example1, are the following:

-   Average Molecular Weight (Mw)=53655 Daltons-   Numerical Molecular Weight (Mn)=35988 Daltons−Polydispersibility=1.5-   Fe³⁺ Content=41.4%

EXAMPLE 4 Preparation of the Ferric Hydroxide-Lactose Complex

50 grams of lactose are dissolved in 250 ml of purified water and to theobtained solution 0.5 g. of sodium bromide are added bringing the pH toa value between 7.0 and 9.0 with a sodium hydroxide solution. Over twohours, 98.5 g. of 12% active chlorine sodium hypochlorite are added,corresponding with the stoichiometric quantity with respect to thealdehyde end groups, maintaining the pH value between 7.0 and 9.0. Atthe end of the addition, the stirring is continued for 30 minutes andthe control of the accomplished activation is carried out through HPLCby detecting the residual lactose and activated lactose ratio.

To the activated lactose solution, brought at a temperature between 16°C. and 20° C., 300 g. of a 40% wt iron chloride solution (iron/sugarratio=1:1.7 w/w) are added continuing the stirring until a completehomogenization of the reaction mixture. Therefore, to the obtainedsolution a 15% w/v sodium carbonate solution is added over 3 hours, soas to slowly bring the PH at a value between 2.3 and 2.7.

When this value has been reached, the solution is maintained understirring and in these conditions over 15 minutes, by checking that thepH value remains between 2.3 and 2.7, and therefore the pH value isbrought to 10.5±0.5 over 1 hour, adding a 15% w/v sodium hydroxidesolution. The precipitation of iron hydroxide never occurs, neither inform of a complex. The obtained solution is purified from the saltsthrough an ultrafiltration system equipped with a membrane with acut-off of 3000 Daltons.

The resulting solution purified from the salts is brought to a pH of11.0±0.5 and heated at a temperature of 75±2° C. for a period of 2 hoursand then after cooling and correction of the pH value at 7, the activesubstance is isolated by spraying.

The physical-chemical features of the complex, with the molecularweights determined according to the methodology described in the example1, are the following:

-   Average Molecular Weight (Mw)−65571 Daltons−numerical molecular    weight (Mn)=40669 Daltons-   Polydispersibility=1.6-   Fe³⁺ Content=49.6%

EXAMPLE 5 Preparation of the Ferric Hydroxide-Polymaltose Complex

70 grams of maltodextrins, characterized by a value of dextroseequivalents equal to 19, are dissolved in 200 ml of purified water andto the obtained solution 1.4 g. of sodium bromide are added.

The pH of the solution is brought to a value between 7.0 and 9.0 with asodium hydroxide solution and over 2 hours, 48.66 g of 12% w/v activechlorine sodium hypochlorite are added, maintaining the pH within thefixed limits. At the end of the addition, the stirring is continued for30 minutes and the accomplished activation is controlled through aHPLC-GPC technique.

To the activated maltodextrin solution, brought at a temperature between16° C. and 20° C., 300 g. of a 40% w/v iron chloride solution(iron/sugar ratio=1:1.7 w/w) are added and the stirring is continueduntil a complete homogenization of the reaction mixture.

Over a period of 5 hours, an aqueous 15% w/v sodium carbonate solution,required for bringing the pH at a value between 2.3 and 2.7 is addedunder stirring, and when this value has been reached the solution ismaintained in these conditions over 15 minutes, by checking that the pHvalue remains between 2.3 and 2.7.

With a 15% w/v sodium hydroxide solution, the pH is brought to the valueof 9.0±0.5 over 1 hour. The precipitation of iron hydroxide neveroccurs, neither in form of a complex.

The obtained solution is purified from the salts through anultrafiltration system equipped with a membrane with a cut-off of 30000Daltons.

The resulting solution is heated at the temperature of 92±2° C. for atime of 3 hours and at a pH of 10.8±0.2.

The cooled solution is brought to pH 6.0±0.5 and then the product isisolated at the dry state through spraying.

The physical-chemical features of the complex are the following:

-   Average Molecular Weight (Mw)=167319 Daltons-   Numerical Molecular Weight (Mn)=69319 Daltons−Polydispersibility=2.4-   Fe³⁺ Content=34.8%

The molecular weights have been determined using the gel-permeationchromatography method which uses a column TOSO HAAS, column modelTSK-GEL G5000PWn 30 cm×7.8 cm ID and, as a standard, dextrans with thefollowing average molecular weights Mw expressed in Daltons: 48600,80900, 147600, 273000, 409800, 667800.

EXAMPLE 6 Preparation of Ferric Hydroxide-Clextran Complex

17.5 grams of dextran, with an average molecular weight between 2000 and7800, are dissolved in 65 ml of purified water and to the obtainedsolution 0.34 g. of sodium bromide are added. The solution is heated at50° C. and the pH is brought at a value between 7.0 and 9.0 with asodium hydroxide solution.

4.14 g. of 12% w/v active chlorine sodium hypochlorite (2 mMoles),corresponding with the double of the dextran moles with an averagemolecular weight of 5000 Da are added over two hours, maintaining the pHvalue between 7.0 and 9.0.

To the activated dextran solution, brought to the temperature of 40° C.or 30° C., 75 g of a 40% w/v iron chloride solution (iron/sugarratio=1:2 w/w) are added, continuing the stirring until a completehomogenization of the reaction mixture.

A 15% w/v sodium carbonate aqueous solution, required for bringing thepH at a value between 2.3 and 2.7 is added over two hours, and when suchvalue has been reached, the reaction mixture is maintained under theseconditions for 30 minutes, controlling that the pH remains constant.

With a 15% w/v sodium hydroxide aqueous solution, the pH value isbrought to 11.5±0.2 over 1 hour and the obtained solution is heated at95±2° C. for three hours and thirty minutes, therefore, after cooling,is purified from the salts through an ultrafiltration system equippedwith a membrane with a cut-off of 400 Daltons, in order to remove thesalts contained.

Once desalted, the solution is maintained at a pH 11.0±0.2, heated atthe temperature of 95±2° C. for a period of at least 5 hours andtherefore cooled at room temperature. The pH of the solution is broughtto the value of 6.0±0.2 and after addition of phenol, stored in sterilecontainers.

The active substance can also be isolated by spraying. The reactionyield is above 85% with respect to the starting iron. Thephysical-chemical features of the complex, with the molecular weightsdetermined according to the methodology described in the example 5, arethe following:

-   Average Molecular Weight (Mw)=226392 Daltons-   Numerical Molecular Weight (Mn)=125590 Daltons-   Polydispersibility=1.8-   Fe³⁻′ Content=36.7%

EXAMPLE 7 Preparation of Ferric Hydroxide-Dextran Complex

17.5 grams of dextran, with an average molecular weight between 2950 and7800, are dissolved in 65 ml of purified water and to the obtainedsolution 0.34 g. of sodium bromide are added. The solution is heated at50° C. and the pH is brought at a value between 7.0 and 9.0 with asodium hydroxide solution.

4.14 g. of 12% w/v active chlorine sodium hypochlorite, correspondingwith the double of the dextran moles with an average molecular weight of5000 Da are added over two hours, maintaining the pH value between 7.0and 9.0.

To the activated dextran solution, brought to the temperature of 50° C.,42.4 g. of a 40% w/v iron chloride solution (iron/sugar ratio=1:3 w/w)are added, continuing the stirring until a complete homogenization ofthe reaction mixture.

A 15% w/v sodium carbonate aqueous solution, required for bringing thepH at a value between 2.3 and 2.7 is added over a period between two andfive hours, and when such value has been reached, the reaction mixtureis maintained under these conditions for 30 minutes, controlling thatthe pH remains constant.

With a 15% w/v sodium hydroxide aqueous solution, the pH value isbrought to 11.5±0.2 over 1 hour and the obtained solution is purifiedfrom the salts through an ultrafiltration system equipped with amembrane with a cut-off of 400 Daltons: in this case, only the existingsalts are removed, not the unreacted excess of dextran. If the removalof all the uncomplexed dextran is desired, then it is necessary to use amembrane with a cut-off of 50000 Daltons.

Once desalted, the solution is maintained at a pH 11.5±0.2, heated atthe temperature of 95±2° C. for a period of at least 5 hours andtherefore cooled at room temperature. The pH of the solution is broughtto the value of 6.0±0.2 and therefore the active substance is isolatedthrough spraying. The reaction yield is above 85% with respect to thestarting iron.

If one desires to maintain the active substance in a solution, phenol isadded and the storage is carried out at 20° C. in sterile containers.

The physical-chemical features of the complex, with the molecularweights determined according to the methodology described in the example5, are the following:

-   Average Molecular Weight (Mw)=205127 Daltons-   Numerical Molecular Weight (Mn)=151276 Daltons-   Polydispersibility=1.4

EXAMPLE 8 Preparation of the Ferric Gluconate Stabilized with Sucrose

To the ferric gluconate solution stabilized and purified from the salts,obtained according to the procedures described in the examples 1 and 2,806 g. of sucrose are added under stirring, a quantity with which theiron/sucrose ratio equal to 1:15.6 is reached.

The solution thus obtained is freeze-dried, giving the ferric gluconatestabilized with sucrose.

EXAMPLE 9 Preparation of the Ferric Hydroxide/Maltose Complex Stabilizedwith Sucrose

To the solution containing the ferric hydroxide/activated maltosecomplex, after purification and stabilization carried out according tothe procedure described in the Example 3, 458 g. of sucrose are addedunder stirring, a quantity with which an iron/sucrose ratio equal to1:15 is reached. The solution thus obtained is freeze-dried, giving thestabilized complex of ferric hydroxide-maltose in a solid form.

1-25. (canceled)
 26. A process for the preparation of an activated sugarFe (III)-complex, wherein said sugar is selected from the groupconsisting of mono- or disaccharide sugars, said process comprising: (a)providing a solution comprising said sugar to be activated and bromine,characterized in that said bromine is produced in situ in the presenceof said sugar to be activated at a pH in the range from 5 to 12 throughthe addition of stoichiometric quantities with respect to the aldehydeend groups of said sugar of a hypochlorite of an alkaline or earthalkaline metal to a solution comprising said sugar to be activated and abromide of an alkaline or earth alkaline metal, wherein the addition ofhypochlorite is carried out instant-by-instant in a way such that allthe added hypochlorite only serves for the bromide oxidation and anexcess of hypochlorite in solution is never present, thereby producingan activated sugar solution, (b) adding a water soluble ferric salt tothe activated sugar solution, such that the resulting solution containsthe activated sugar and the iron (III) salt in an iron to sugar weightratio between 1:0.5 and 1:5, whereafter the pH of the solution iscontrolled at a value between from 2.3 to 2.7 by adding a sodiumhydrogencarbonate or a sodium carbonate solution in a time between 1 and6 hours; (c) bringing the pH of the solution as per step (b)subsequently to a value between 8 and 12, to give a solution containingthe Fe (III)-activated sugar complex, and (d) purifying the Fe(III)-activated sugar complex.
 27. The process according to claim 26,wherein the pH in step (a) is between 6 and
 11. 28. The processaccording to claim 27, wherein the pH in step (a) is between 7.0 and9.0.
 29. The process according to claim 26, wherein, in step (a), thehypochlorite is sodium hypochlorite and the bromide is sodium bromide.30. The process according to claim 29, wherein said sugar to beactivated is selected from the group consisting of glucose, maltose, andlactose.
 31. The process according to claim 26, wherein the solution instep (a) is an aqueous solution including said sugar to be activated ina quantity between 10 and 50% by weight, based on the weight of thesolution.
 32. The process according to claim 31, wherein the quantity ofbromide in step (a) is between 0.5 and 5% by weight, based on the totalweight of said sugar to be activated.
 33. The process according to claim26, wherein the hypochlorite added in step (a) is in an aqueous solutioncontaining about 12% by weight of active chlorine.
 34. The processaccording to claim 26, wherein said ferric salt in step (b) is irontrichloride hexahydrate.
 35. The process according to claim 26, whereinthe solution in step (b) contains the activated sugar and the iron (III)salt in the iron to sugar weight ratio from 1:0.5 to 1:4.
 36. Theprocess according to claim 26, wherein the pH of the solution in step(b) is controlled by adding a sodium hydrogencarbonate solutioncontaining 15% w/v sodium hydrogencarbonate.
 37. The process accordingto claim 26, wherein the pH of the solution as per step (b) issubsequently brought in step (c) to the value between 8 and 12 throughthe addition of a sodium hydroxide solution.
 38. The process accordingto claim 26, wherein the purification in step (d) is carried out byultrafiltration with a membrane having a cut-off between 3000 and 5000Daltons.
 39. The process according to claim 38, wherein the Fe(III)-activated sugar complex as per step (c) or (d) is stabilized in afurther step (c′) or (e) by heating of the solution containing the sameat a temperature between 60° C. and 100° C., for a period between 1 and4 hours at a pH between 9.0 and 12.0.
 40. The process according to claim39, wherein the Fe (III)-activated sugar complex is selected from thegroup consisting of iron gluconate, iron lactate and iron maltosestabilized with sucrose.
 41. Fe (III) and activated sugar complexobtainable according to a preparation process according to claim
 26. 42.Use of a Fe (III) and activated sugar complex according to claim 41 forthe preparation of a medicinal speciality for the treatment of irondeficiency conditions.
 43. Use according to claim 42, wherein thetreatment is directed to pathologies such as: functional iron deficiencyin patients suffering from a renal chronic failure, bad absorption ofthe iron due to intestinal diseases, chronic blood loss also togetherwith erythropoietin and constitutional anemia.
 44. The process accordingto claim 27, wherein the pH in step (a) is between 7 and
 10. 45. Theprocess according to claim 39, wherein said Fe (III)-activated sugarcomplex as per step (c) or (d) is stabilized in a further step (c′) or(e) by heating of the solution containing the same at a temperaturebetween 75° C. and 95° C.